Cyclic Nucleotide Responses Research Articles

Studies on the dynamics of adrenocortical responses to ACTH in the rat

The transient dynamics of plasma ACTH, adrenal cyclic AMP, adrenal corticosterone and plasma corticosterone were evaluated in male Sprague-Dawley rats, whose endogenous release of ACTH had been blocked by dexamethasone: (1) 40 min after single injections of ACTH ranging from 2 to 300 ng ACTH/100 g B.W., i.V.; (2) at time intervals after single injections of 9, 37 and 300 ng ACTH/100 g B.W.; (3) during and after prolonged infusion of 4 ng ACTH/min/100 g B.W. Plasma corticosterone concentration was still at a nearly maximal level 40 min after the injection of ACTH at a dose level for which the adrenal cyclic AMP content had fallen back to a value that was scarcely above the control one; a narrow window, defined by a 2-fold increase in the dose of ACTH, represents the transition between a minimal and a maximal adrenal cyclic AMP content. The adrenal cyclic AMP transient response after injection of graded doses of ACTH increased rapidly to a peak whose amplitude was dose-dependent; the duration of the cyclic nucleotide response, however, appeared to be independent of the ACTH dose level. The adrenal corticosterone content rose rapidly, and the eventual fall was delayed by increasing doses of ACTH. The time course of the early plasma corticosterone concentrations exhibited a similar rate of increase after any dose of ACTH; in any case, a steady state whose duration was dose-dependent was eventually reached and the ensuing fall therefrom occurred at a time when the adrenal cyclic AMP had fallen to very low levels. The adrenal cyclic AMP content showed an overshoot at a time when ACTH and corticosterone had reached a constant steady state, during a prolonged infusion of ACTH; adrenal cyclic AMP stabilized during the later phase of the infusion. After removal of the infusion, plasma ACTH levels fell relatively slowly as compared with adrenal cyclic AMP, whereas corticosterone remained at a maximal level for at least 120 min. Our results, derived from experiments in vivo, support the recent proposal by Bristow et al. (1980), derived from studies in vitro, that ACTH can act via either of two types of receptor: binding to one receptor elicits steroidogenesis via cyclic AMP production whereas binding to the other receptor elicits steroidogenesis through some other mechanism.

Cyclic Nucleotide Response to Stimulation in Isolated Glomeruli from Dog Kidney

The effects of biogenic amines on cyclic 3',5'-adenosine monophosphate (cAMP) and on cyclic 3',5'-guanosine monophosphate (cGMP) were studied in isolated glomeruli from dog kidneys. Of the agents tested, histamine produced the greatest increase in cyclic nucleotide activity. Isoproterenol, dopamine, epinephrine and norepinephrine also produced increases in cAMP and/or cGMP activity but of lesser magnitude. Propranolol decreased cyclic nucleotide levels. Glomeruli isolated from the outer cortex showed greater responses to stimulation than glomeruli from the inner cortex.

Hepatic effects of glucose and insulin independent of cyclic nucleotide changes.

To determine if cGMP might function as a second messenger for insulin, an in situ liver perfusion system was established in which hepatic effects of insulin could be correlated with changes in cyclic nucleotides. Several combinations of insulin (10 mU/ml) and glucose (50 mg/ml) were infused (0.1 ml/min) for 30 min into fasted normal and diabetic rats with removal of a similar volume of blood. Samples of livers were removed at the beginning and end and at various times during the perfusion. In normal animals perfused with buffer alone, hepatic glycogen content fell. When glucose (with or without added insulin) was added to the perfusate, glycogen levels rose. With buffer alone, there was no change in the independent (I) form of glycogen synthase at 10 min but a modest increase at 30 min. With insulin and/or glucose, there as a large increase in the I-form of the enzyme at 10 min and a further rise at 30 min. Neither cGMP nor cAMP changed even though tissue samples were obtained at multiple times throughout the perfusion. Cyclic nucleotides were also measured in liver slices exposed to insulin (1 mU/ml) after 30 min of pre-incubation for stabilization. Although significant increases in cGMP were noted in the tissue exposed to insulin, similar significant rises also occurred in appropriately paired control slices. When glucagon was used in both the in situ perfusion and the paired liver slice systems, the expected rapid and large increases in cAMP levels occurred attesting to the validity of both approaches in evaluating hepatic cyclic nucleotide responses. These results plus the paucity of convincing data in the literature strongly suggest that cGMP can no longer be considered a candidate for the putative second messenger of insulin.

Airway and metabolic responsiveness to intravenous salbutamol in asthma: effect of regular inhaled salbutamol.

1. Airway, metabolic and cyclic nucleotide responses to intravenous salbutamol were measured in five patients with mild asthma who had taken no medication in the week before the study. The studies were repeated after the patient had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 2000 micrograms daily in week 4. 2. The pretreatment airway, metabolic and cyclic nucleotide responses to salbutamol were similar to those previously reported in normal subjects. These patients therefore did not show evidence of partial beta-adrenoceptor blockade. 3. After 4 weeks' salbutamol therapy the airway response to intravenous salbutamol was unchanged. 4. The glucose, pyruvate and adenosine 3':5'-cyclic monophosphate (cyclic AMP) responses to intravenous salbutamol were depressed after regular salbutamol administration. The dose-response curve for non-esterified fatty acids and insulin, though displaced downwards, did not indicate an impaired response to salbutamol since the shape was unchanged. There was no significant change in the lactate, glycerol and total ketone response. 5. This study confirms that tissues differ in the ease with which they develop resistance to beta-adrenoceptor agonists. Asthmatic airways appear to be relatively protected from developing assistance when compared with other tissues in asthmatic patients and when compared with the airways of normal subjects.

Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purkinje cell degeneration in pcd mutant mice.

The Purkinje cell degeneration mutant (pcd) is characterized by a complete loss of cerebellar Purkinje cells. Norepinephrine causes an accumulation of cyclic AMP in the cerebellum of pcd that is far greater than in normal mice. Experiments were conducted 1) to correlated changes in the cyclic-nucleotide response with a histologic examination of the cerebellum during neuronal loss and 2) to examine the role of cyclic AMP catabolism and adenosine receptor interactions in the phenomenon. The greatest elevation in cyclic AMP occurred between 30 and 128 days of age when a severe astrocytic response was demonstrated throughout the cerebellar cortex. Purkinje cells had degenerated by 45 days of age. Norepinephrine elicited a smaller increase in cyclic AMP from 155-day-old mice than at earlier ages, and the response continued to decrease with age; at 270 days, equal accumulation, and at 365 days. lower accumulation of cyclic AMP was detected in pcd cerebella. During this time, the Purkinje cell debris had been removed, the granule cell layer was depleted of granule cells, and the molecular layer was deprived of a large number of parallel fibers. However, although phagocytosis of neuronal debris was completed, large numbers of astrocytic processes were still seen in the neuropil. Biochemical experiments in vitro established that the exaggerated accumulation of cyclic AMP in the presence of norepinephrine was not due to lower catabolism of cyclic AMP, a synergistic interaction with adenosine, or a result of lower protein in the pcd cerebellum. The correlates of heightened norepinephrine-stimulated accumulation of cyclic AMP with neuronal loss and the glial cell reaction might indicate that cyclic nucleotides play a role in controlling some glial cell functions, ie, proliferation, migration, and phagocytosis.

Gonadotropin-releasing hormone inhibits cyclic nucleotide accumulation in cultured rat granulosa cells.

Ovarian granulosa cells obtained from hypophysectomized, diethylstilbestrol-treated rats were cultured in the presence of ovine follicle-stimulating hormone (FSH) and gonadotropin-releasing hormone (GnRH). FSH stimulated the production and accumulation of both cAMP and cGMP, as well as progesterone, during a 48-h incubation period. Addition of GnRH or an agonist analog, [D-Ala6]des-Gly10-GnRH N-ethylamide (GnRHa), did not influence the cyclic nucleotide response to FSH in the first 6 h of incubation, but caused dose-dependent inhibition of the FSH-induced rise in cyclic nucleotide production from 24 to 48 h of incubation. Cellular production of both cyclic nucleotides and progesterone was decreased by GnRHa concentrations as low as 10(-12) M, with maximum inhibition at 10(-9) M GnRHa. These results suggest that the in vitro antigonadal actions of GnRH and related peptides are expressed through inhibition of cyclic nucleotide production.

Choleragen-induced cyclic nucleotide response in a lower eukaryote

sustained increase in the CAMP level of tissues, cells [4,5 ] and isolated membranes [6,7]. The cellular CAMP level elevated by choleragen is often associated with the acquisition by many cultured cells of differentiation characteristics and/or inhibition of proliferation [8,9], though in some instances this elevation has been associated with initiation of proliferation [lo]. Steps in the mechanism of action of the toxin, as now understood, include the characteristic binding of the choleragen B protomer to the C,, ganglioside [ 11,121 located in the plasma membrane, the disul- fide reduction to release the A, subunit from the A protomer [ 13,141 and the Ar subunit-facilitated ADP-ribosylation of a GTP-binding regulatory unit of the membrane-bound adenyl cyclase. ADP ribosyla- tion, with NAD as donor [IS], is thought to interdict the normal control function of the regulatory unit of adenyl cyclase, leaving the enzyme in the activated state. We have found that choleragen induces a change in the calcium~ontro~ed H*-permeability ] 16,171, mimicking that produced by light [ 181 as well as by dibuty~1 CAMP or caffeine [ 19-2 I]. This reaction appears to be closely related to photoreception in the light-induced sporulation of

Brain Cyclic Nucleotide Responses to Anesthesia With Halothane Delivered in Air or Purified Oxygen

Inhalation of either 0.5% or 1.0% halothane in air caused a slight decrease in the cAMP concentration in rat cerebral cortex and cerebellum. During recovery, concentrations returned to normal in 3 h, or less. In contrast, cGMP decreased sixfold in cerebellum, but increased twofold in cortex. Recovery time for cerebellum was several hours. When oxygen was used as the carrier gas for halothane delivery, cAMP in the cortex doubled, in striking contrast to the case with halothane in air. Oxygen alone had no apparent effect. The cGMP effect of halothane delivered in oxygen appeared the same as for halothane in air. Thus, the cAMP effects of brain halothane are related to the enrichment of oxygen.

Plasma cyclic nucleotide responses to insulin-induced hypoglycaemia and methacholine in patients with hyperthyroidism.

The effect of insulin-induced hypoglycaemia and methacholine on plasma cAMP and cGMP levels was studied in normal volunteers, hyperthyroid and hypothyroid patients. A significant positive correlation existed between the maximal increase in plasma cAMP and the maximal decrease in plasma glucose in normals during insulin-induced hypoglycaemia. Therefore, the plasma cAMP response is considered to be dependent on the degree of hypoglycaemia, rather than the dose of insulin. The cAMP response to hypoglycaemia was significantly higher in hyperthyroid patient, and was lower in patients with hypothyroidism than in normals. The cAMP response of the hyperthyroid patients was normalized when their hyperthyroidism was controlled after 3 months of treatment. The plasma level of cGMP was slightly elevated during hypoglycaemia, but there was no significant difference between controls and hyperthyroid patients. The cGMP response to methacholine, which is probably mediated by cholinergic receptors, was significantly potentiated in hyperthyroid patients. The cAMP response, which is presumably dependent on endogenous catecholamines secreted during methacholine-induced hypotension, was also enhanced in hyperthyroid patients. It is likely that beta-adrenergic receptor responses and cholinergic receptor responses are both enhanced in hyperthyroidism.

Hyposensitization and the Bronchial Responsiveness to Histamine and Plasma Cyclic Nucleotide Response to Adrenalin in Asthmatic Children

Hyposensitization and the Bronchial Responsiveness to Histamine and Plasma Cyclic Nucleotide Response to Adrenalin in Asthmatic Children

Catecholamine and cyclic nucleotide response of sheep to the injection of Clostridium welchii type D epsilon toxin

Injection of Clostridium welchii (C. perfringens) type D epsilon toxin into sheep caused large increases in catecholamine and cyclic adenosine 3',5'-monophosphate levels and moderate increases in cyclic guanosine 3',5'-monophosphate levels. Haemoconcentration also occurred. It is suggested that a rapidly developing brain oedema is the stimulus for a release of catecholamines which in turn activates adenyl cyclase. The resulting rise in cAMP causes glycogenolysis and hyperglycaemia.

Beta-adrenergic stimulation of cyclic AMP content and parathyroid hormone release from isolated bovine parathyroid cells.

The effects of beta-adrenergic agonists and antagonists on cyclic AMP (cAMP) accumulation and parathyroid hormone (PTH) release from isolated bovine parathyroid cells have been determined. Beta-adrenergic agonists markedly stimulate cAMP production and PTH release with an order of potency (-) isoproterenol greater than (-)epinephrine greater than greater than (-) norepinephrine, suggesting a beta2-type adrenergically mediated process. Both effects are blocked by the beta-blocker propranolol with the strict stereospecificity expected for a beta-adrenergic response. Low calcium concentrations also stimulate cAMP accumulation, but the cyclic nucleotide response under these conditions is only 3% of that obtained with isoproterenol, raising the possibility that factors other than cAMP may control low calcium-mediated PTH release. The release of PTH by low calcium is also not blocked by propranolol, confirming the independence of the response to low ambient calcium from the beta-adrenergic receptor. These studies substantiate further the utility of the isolated parathyroid cell preparation for studying secretagogue-mediated alterations in cyclic nucleotides and hormone secretion. Isolated cells also also make feasible the direct identification of beta-adrenergic receptors in parathyroid cell membranes and whole cells.

In vitro behavior of human intestinal mucosa. The influence of acetyl choline on ion transport.

The possibility that the autonomic nervous system may influence the function of intestinal mucosa was investigated by assessing the effect of acetyl choline on ion transport in human intestine. Isolated pieces of stripped ileal mucosa were mounted in Perspex flux-chambers and bathed in isotonic glucose Ringer's solution. Acetyl choline caused a rise in mean potential difference (8.8-12.3 mV, P less than 0.002) and short circuit current (287.7-417.2 muA-cm-2, P less than 0.01) (n = 12), observable at a concentration of 0.01 mM and maximal at 0.1 mM. This effect was enhanced by neostigmine and blocked by atropine. Isotopic flux determinations revealed a change from a small mean net Cl absorption (58) to a net Cl secretion (-4.3mueq-cm-2-h-1P less than 0.001) due predominantly to an increase in the serosal to mucosal unidirectional flux of Cl (10.63-14.35 mueq-cm-2-h-1P less than 0.05) and a smaller reduction in the mucosal to serosal flux (11.22 to 10.02 mueq-cm-2-h-1P less than 0.05). Unidirectional and net Na transport was unaffected. A similar electrical and ion transport response was observed in a single study of two pieces of jejunal mucosa. In the absence of glucose net chloride secretion was produced and again an insignificant effect on net sodium transport was noted. Acetyl choline did not provoke a sustained effect on mucosal cyclic adenine nucleotide levels although a short-lived cyclic adenine nucleotide response was seen in some tissues 20-30 s after drug addition. These studies demonstrate that acetyl choline does influence human intestinal ion transport by stimulating chloride secretion and suggest a possible mechanism by which the parasympathetic nervous system could be concerned in the control of ion transport.

Mucosal cyclic AMP and secretion in the dog stomach.

ARTICLESMucosal cyclic AMP and secretion in the dog stomachCC Mao, ED Jacobson, and LL ShanbourCC Mao, ED Jacobson, and LL ShanbourPublished Online:01 Oct 1973https://doi.org/10.1152/ajplegacy.1973.225.4.893MoreSectionsPDF (967 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByInhibitors of gastric secretion: Current progress7 December 2005 | British Journal of Surgery, Vol. 63, No. 10Intracellular Activation Events for Parietal Cell Hydrochloric Acid Secretion1 January 2011The adenylate cyclase-cyclic AMP-protein kinase system in different cell populations of the guinea pig gastric mucosaLife Sciences, Vol. 37, No. 12CYCLIC AMP AND GASTRIC ACID SECRETION IN THE DOGANZ Journal of Surgery, Vol. 52, No. 3A Role of Cyclic AMP in the Gastrointestinal Tract: Receptor Control of Hydrogen Ion Secretion by Mammalian Gastric MucosaHistamine Receptors and Cyclic NucleotidesCyclic nucleotide response to acid-secreting stimuli in guinea pig gastric mucosa in vitroGastroenterologia Japonica, Vol. 16, No. 4Cyclic nucleotides and the regulation of canine gastric acid secretionDigestive Diseases and Sciences, Vol. 24, No. 4Effects of Ethanol on Membrane TransportEffect of the phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711) on gastric secretion and gastric mucosal cyclic AMPNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 304, No. 1Effect of Ca2+, Mg2+, NaN3, cholinergic agents, and gastrointestinal hormones on the guanylate cyclase from guinea pig gastric mucosaGastroenterology, Vol. 74, No. 2Prostaglandins and Gastrointestinal Secretion and MotilityInterrelationships Between Histamine, Prostaglandins, and Cyclic AMP in Gastric Secretion: A HypothesisGastroenterology, Vol. 73, No. 4Cyclic nucleotide activity in gastrointestinal tissues and fluidsAnalytical Biochemistry, Vol. 78, No. 2Histamine, cyclic AMP, and gastric secretion in the dogThe American Journal of Digestive Diseases, Vol. 22, No. 1Cyclic adenosine monophosphate and human gastric acid secretionThe American Journal of Digestive Diseases, Vol. 22, No. 8Characterization of an adenylate cyclase system sensitive to histamine H2-receptor excitation in cells from dog gastric mucosaAgents and Actions, Vol. 6, No. 6Effects of Secretagogues on Oxygen Consumption, Aminopyrine Accumulation and Morphology in Isolated Gastric GlandsActa Physiologica Scandinavica, Vol. 97, No. 4Gastric acid secretionThe American Journal of Digestive Diseases, Vol. 21, No. 5Distribution of adenyl cyclase sensitive to histamine in rabbit gastric mucosaBiochemical Pharmacology, Vol. 25, No. 5Action of H 1 and H 2 Inhibitors on the Response of Histamine Sensitive Adenylyl Cyclase from Guinea-Pig MucosaEuropean Journal of Clinical Investigation, Vol. 6, No. 1Stimulation of adenylate cyclase of guinea pig gastric mucosa by histamine, sodium fluoride and 5?-guanylylimidodiphosphate and inhibition by histamine H1- and H2-receptor antagonists in vitroNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 296, No. 1Effects of Cyclic Adenosine 3':5'-Monophosphate and Related Agents on Acid Secretion by Isolated Rabbit Gastric MucosaGastroenterology, Vol. 69, No. 2Modulation of Stimulated Acid Secretion by Dibutyryl Cyclic Amp in the Dog StomachGastroenterology, Vol. 69, No. 1Action of Insulin on Some Other Organs and on DifferentiationCyclic Nucleotides and their Role in Gastrointestinal SecretionGastroenterology, Vol. 67, No. 5Rat gastric mucosal cAMP following cholinergic and histamine stimulationEuropean Journal of Pharmacology, Vol. 28, No. 2STIMULATION OF RAT GASTRIC ADENYLATE CYCLASE BY HISTAMINE AND HISTAMINE ANALOGUES AND BLOCKADE BY BURIMAMIDE19 July 2012 | British Journal of Pharmacology, Vol. 52, No. 1 More from this issue > Volume 225Issue 4October 1973Pages 893-896 Copyright & PermissionsCopyright © 1973 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1973.225.4.893PubMed4355179History Published online 1 October 1973 Published in print 1 October 1973 Metrics

Cyclic AMP in the regulation of gastric secretion in dogs and humans.

Cyclic AMP in the regulation of gastric secretion in dogs and humans.